Making the best of research investment in pathogens control through biocontrol. How is research correlated with agricultural microbial biological control product availability?

While using microbial biological control products (MBCPs) to limit pathogens is one of the alternatives to the ecologically unsustainable use of synthetic pesticides that received attention, the last 2 decades have not brought the foreseen leap in developing systematic alternatives based on low-risk plant protection products (PPPs) across the globe. To explain this limited progress, we map the evolution of research on the most successful microbial biological control agents (MBCAs) worldwide. We also map the financing structure in the top funding countries and the European Union (EU) to discern the relevant trends. Available data for the European Union Member States allowed us to discover a country-level and EU-level correlation between strain-level research and biocontrol products’ approval based on those strains.


Why is the research-microbial biological biocontrol product (MBCP) development nexus important?
In controlling plant pathogens [1], compared to synthetic pesticides, biological control agents (BCAs) have multiple advantages, like the positive impact on yields, and the health of crops, minimal adverse effects on farmworkers' and communities' health, the absence of harvesting pause or re-entry period characteristic of chemical pesticides use, and positive public perception [2]. The biocontrol industry has grown in the last decades but reached a worldwide market of only US$1.5 billion [3] and 3.6 billion euros in 2022, of which 800 million euros in the European Union (EU) [4]. It is projected to increase to US$7.5 billion by 2025 [5] but will still represent only 2% of the synthetic pesticides market. Unlike invertebrate BCAs, which generally need no registration and approval, employing microbial biological control agents (MBCA) is highly controlled in developed countries. Despite aiming to promote low-risk alternatives [6], the EU has a more costly and time-consuming double-stage procedure (microbial strain approval at the EU level and product authorization at the national level) [7]  were labeled low-risk substances [8], the European Food Safety Authority published several pesticide risk assessments to accelerate developments and decrease barriers, and MBCA approval accelerated [9,10]. Nevertheless, factors like the cost of patents, high specificity of the products, costs of product registration, complex application of MBCP, more elaborate production and storage processes [11], the difficulties in identifying efficient strains, and the complex development process leading to efficient microbial biological control products (MBCP), still hamper the development of the sector. Consequently, the fundamental and applied research in biocontrol is one of the most significant ways the scientific community can contribute to agriculture's sustainability and decrease the time between the appearance of new diseases and the development of new MBCP [12].

How to evaluate the link?
Studying this relationship is easier said than done, as the limited data availability imposes severe limitations. We have employed Claryvate Analytics Web of Science (WoS) with subcollections to map research and funding evolution. It rigorously identifies the country of the author's institutions and the funding agency. WoS allows complex search syntax for labeling articles on biocontrol. WoS's disadvantage is that only the titles, keywords, and abstracts are introduced, not the article's whole body. As only the species used in experiments are mentioned in the abstract but not the strains, only species-level labeling of the article is possible. As WoS does not allow strain-level search, we have employed Google Academic (GA), the most exhaustive database containing many articles' content. Nevertheless, GA is less rigorous, does not have a unique identification number for articles, and cannot differentiate between authors' countries or funding agencies.

How fragmented is funding, and what country's agencies dominate funding?
First, we aimed to establish to what extent the country and financing agencies of biocontrol research have changed in the last 2 decades. We treat the EU as a region because, unlike the other major markets with a one-step registration process, the EU has 2 stages of the procedure. Furthermore, EU MS can access funding for research through European funds. In a recent article, we used WoS data to show that 2007 marked a turning point in the EU's and China's approach to biocontrol, as the number of articles exceeded those published by US-based scientists [10]. Here, we investigate if this change in publications is linked to the financing structure of MBCA research.
Data on funding sources for biocontrol articles in WoS between 2005 and 2018 shows that the research is highly fragmented, as 73.4% of grant institutions funded only 1 article, 11.7% 2, and 5.8% 3 articles. Just 1.4% (15 in total) of granting institutions supported more than 6 articles in biocontrol. Out of the 1,077 agencies identified as financing biocontrol-related research published in WoS-indexed articles, the highest number of programs (around 182) and 7 out of the 12 top are Chinese. EU grants are coming only in fifth place, while the USA's Department of Agriculture (6th place), Department of Health and Human Services (9th place), and National Science Foundation (11th place) are trailing. Not unexpectedly, the national and multinational corporations have rarely financed published research in biocontrol (Bayer-14 mentions, Novartis-10 mentions, Merk-10 mentions, BASF-1 mention, Monsanto, Syngenta, Koppert-no mention). Results underline the fragmentation of biocontrol research funding. Fragmentation prevents the continuous funding of research through the bioproduct cycle from strain identification to production and limits identifying common research priorities [13].

Is research correlated with product authorization?
Second, we studied if country-level biocontrol research on specific microbial species is correlated with country-level MBCP authorization based on the same species in the EU. We focused only on the 28 EU Member States (MS), as we could collect strain-level data for bivariate statistics using data from GA and the EU Pesticides database [14]. In

Does research focus on strains already proven successfully useful for pathogens control?
Third, we increased our evaluation's resolution by testing the correlation between biocontrol research at the strain level (number of articles from 2010 to 2020) and the number of countries where products based on that strain were authorized. Testing the correlation was possible only for Bacillus thuringiensis, Bacillus amyloliquefaciens, and Beauveria bassiana. Data in the last column in Table 2 shows that the correlation is very high in all 3 cases. It indicates that at this level, too, basic research is more focused on those strains that are already proven successful for pathogen control, a highly counter-intuitive finding. We also highlighted (with bold) if the year a strain is approved in the EU leads to increased articles published on those microbial strains (we included data for some other 4 species). A clear pattern emerges: strain-level   research accelerates after approval at the EU level (first stage). This finding indicates that the potential to be fastly used as a strain in biopesticides increases researchers' interest and the possibility of attracting funding.

Conclusions
Data shows a clear intensifying of biocontrol-related research, especially in the EU and China, compared with the US, after 2006. However, financing for this research is very fragmented across different agencies and programs. Only China has a consistent set of larger financing agencies. The US is trailing in total publications on biocontrol, research on the most successfully used in biocontrol microbial strains, and financing.
For the species that generated the highest interest in the number of authorized MBCP in the EU MS, the increase in research intensity is evident compared with other countries investigated in approved strains and the number of countries approving products. Furthermore, strain-level research also appears to be correlated with the success of MBCPs authorization based on those strains.   The positive correlation between increased biocontrol research and MBCP authorization could provide a virtuous circle that could sustain an exponential increase of MBCP availability in the next decade, products that, in combination with improved recent legislation [15], the introduction of Integrated Pest Management (IPM) and organic agriculture, could set the path for a more sustainable and environmentally friendly effort to control pathogens. The fragmentation pattern in financing biocontrol research in the EU and the USA probably prevents identifying some priorities. It also prevents faster sampling cycles, strain isolation, and selection, patenting, assessment, storage and formulation, and product registering.